tbuckley/cabot-search huggingface dataset:
Abstract IA24: IDH Inhibitors: Rationale, Molecular Mechanisms and Benefit
Authors: Andrew X. Zhu
Journal: Clinical Cancer Research (2022)

Abstract Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are the most frequently mutated metabolic genes across human cancers including cholangiocarcinoma. These hotspot gain-of-function mutations will lead to the IDH enzyme to aberrantly produce high levels of R-2-hydroxyglutarate (2-HG), which is thought to be the oncometabolite. 2-HG can competitively inhibit enzymes that regulate epigenetics, DNA repair, metabolism, and it can also modulate tumor immune microenvironment. IDH-1 mutations are particularly common in intrahepatic cholangiocarcinoma (iCCA), and their frequency varies depending on the geographic location and underlying etiology. Many inhibitors targeting mutant IDH (mIDH) are under active clinical development. Results from the phase III ClarIDHy trial have demonstrated that ivosidenib-a first-in-class, oral, small-molecule inhibitor of mutant IDH1, was well tolerated and could improve progression-free survival and a favorable overall survival benefit versus placebo, leading to the regulatory approval of ivosidenib in mIDH1 cholangiocarcinoma. The author will discuss the rationale, current clinical development, unanswered questions including the mechanism of resistance, and the optimal combination strategies that can more effectively harness mIDH as a therapeutic target. Citation Format: Andrew X. Zhu. IDH Inhibitors: Rationale, Molecular Mechanisms and Benefit [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA24.
Millions of children face a “humanitarian crisis” of fuel poverty
Authors: Michael Marmot, Ian Sinha, Alice Lee
Journal: BMJ (2022)

By January 2023 more than half of UK households, 1 including millions of children, will be in fuel poverty unless effective interventions are established.Our concern is with the health effects of this crisis, in particular its effects on certain groups at risk: black and ethnic minority groups, households with children, people on low incomes, and people with disabilities. 2Fuel poverty is driven by the energy efficiency of a home, household income, and the cost of fuel.Substandard housing and insufficient income are deep rooted problems in the UK, and more than a third of children live in poverty.Energy prices are soaring.This winter, fuel poverty and cold homes will present a public health and humanitarian crisis.
Oncogenic Transformation of Human Mammary Epithelial Cells by Autocrine Human Growth Hormone
Authors: Tao Zhu, B. Starling-Emerald, Xin Zhang, Kok-Onn Lee, Peter D. Gluckman, Hichem C. Mertani, Peter E. Lobie
Journal: Cancer Research (2005)

Abstract The human growth hormone (hGH) gene is expressed in the normal human mammary epithelial cell and its expression increases concomitant with the acquisition of proliferative lesions. Herein we demonstrate that autocrine production of hGH in human mammary carcinoma cells dramatically enhances anchorage-independent growth in a Janus kinase 2–dependent manner. Forced expression of the hGH gene in immortalized human mammary epithelial cells increased proliferation, decreased apoptosis, altered the cellular morphology and resulted in oncogenic transformation. Autocrine hGH was therefore sufficient to support anchorage-independent growth of immortalized human mammary epithelial cells and tumor formation in vivo. Moreover, autocrine hGH disrupted normal mammary acinar architecture with luminal filling and deregulated proliferation in three-dimensional epithelial cell culture. Autocrine hGH utilized homeobox A1 to govern the transcriptional program required for autocrine hGH–stimulated oncogenic transformation of human mammary epithelial cells, including transcriptional up-regulation of c-Myc, cyclin D1, and Bcl-2. Forced expression of a single orthotopically expressed wild-type gene is therefore sufficient for oncogenic transformation of the immortalized human mammary epithelial cell.
Limited Effects of HIV Counseling and Testing for Women
Authors: Jeannette R. Ickovics
Journal: JAMA (1994)

<h3>Objectives.</h3> —To assess the consequences of human immunodeficiency virus (HIV) counseling and testing for seronegative women in terms of sexual behavior and psychological outcomes. <h3>Design.</h3> —The design is prospective and longitudinal, using repeated measures. Participants were interviewed at recruitment, 2 weeks later (when tested women received results), and 3 months later. <h3>Setting.</h3> —Four community health clinics in southern Connecticut; all provide HIV counseling and testing and other specialized and primary health care services. <h3>Study Participants.</h3> —A sequential sample of women were recruited for two study groups: those seeking HIV counseling and testing (n=152), and a comparison group never tested for HIV (n=78), matched by clinic, race, and age. <h3>Main Outcome Measures.</h3> —A composite measure of sexual risk was developed, based on sexual activity, condom use, and partner risk factors. Psychometrically valid and reliable measures of general psychological functioning and acquired immunodeficiency syndrome (AIDS)—specific psychological indicators were also used. <h3>Results.</h3> —Average level of sexual risk was lower for tested than nontested women at all three interviews. For both groups, there was no significant change in sexual risk from baseline to 3-month follow-up. At the individual level, there was no difference in the number of women who decreased or increased sexual risk. For tested women, intrusive thoughts about AIDS and estimated chance of getting AIDS decreased after counseling and testing. <h3>Conclusions.</h3> —Behavioral and psychological consequences of HIV counseling and testing for women at risk for HIV were limited. These results have implications for further prevention interventions. (<i>JAMA</i>. 1994;272:443-448)
Menopause and the Risk of Coronary Heart Disease in Women
Authors: Graham A. Colditz, Walter C. Willett, Meir J. Stampfer, Bernard Rosner, Frank E. Speizer, Charles H. Hennekens
Journal: New England Journal of Medicine (1987)

To determine the relation of menopause to the risk of coronary heart disease, we analyzed data on a prospective cohort of 121,700 U.S. women 30 to 55 years old who were followed from 1976 to 1982. Information on menopausal status, the type of menopause, and other risk factors was obtained in 1976 and updated every two years by mailing questionnaires. Through 1982, the follow-up rate was 98.3 percent for mortality and 95.4 percent for nonfatal events. After we controlled for age and cigarette smoking, women who had had a natural menopause and who had never taken replacement estrogen had no appreciable increase in the risk of coronary heart disease, as compared with premenopausal women (adjusted rate ratio, 1.2; 95 percent confidence limits, 0.8 and 1.8). Again compared with premenopausal women, the occurrence of a natural menopause together with the use of estrogens did not affect the risk (rate ratio, 0.8, 95 percent confidence limits, 0.4 and 1.3). Women who had undergone bilateral oophorectomy and who had never taken estrogens after menopause had an increased risk (rate ratio, 2.2; 95 percent confidence limits, 1.2 and 4.2). However, the use of estrogens in the postmenopausal period appeared to eliminate this increased risk among these women as compared with premenopausal women (rate ratio, 0.9; 95 percent confidence limits, 0.6 and 1.6). These data suggest that, in contrast to a natural menopause, bilateral oophorectomy increases the risk of coronary heart disease. This increase appears to be prevented by estrogen-replacement therapy. (N Engl J Med 1987; 316:1105–10.)
Prevalence of HIV Infection in Childbearing Women in the United States
Authors: Marta Gwinn
Journal: JAMA (1991)

A national, population-based survey was initiated in 1988 to measure the prevalence of human immunodeficiency virus (HIV) infection in women giving birth to infants in the United States. Following standardized procedures, residual dried-blood specimens collected on filter paper for newborn metabolic screening were tested anonymously in state public health laboratories for maternal antibody to HIV. As of September 1990, annual survey data were available from 38 states and the District of Columbia. The highest HIV seroprevalence rates were observed in New York (5.8 per 1000), the District of Columbia (5.5 per 1000), New Jersey (4.9 per 1000), and Florida (4.5 per 1000). Nationwide, an estimated 1.5 per 1000 women giving birth to infants in 1989 were infected with HIV. Assuming a perinatal transmission rate of 30%, we estimate that approximately 1800 newborns acquired HIV infection during one 12-month period. Preventing transmission of HIV infection to women and infants is an urgent public health priority. (<i>JAMA</i>. 1991;265:1704-1708)
Brief Physician Advice for Problem Alcohol Drinkers
Authors: Michael F. Fleming
Journal: JAMA (1997)

<h3>Objective.</h3> —Project TrEAT (Trial for Early Alcohol Treatment) was designed to test the efficacy of brief physician advice in reducing alcohol use and health care utilization in problem drinkers. <h3>Design.</h3> —Randomized controlled clinical trial with 12-month follow-up. <h3>Setting.</h3> —A total of 17 community-based primary care practices (64 physicians) located in 10 Wisconsin counties. <h3>Participants.</h3> —Of the 17 695 patients screened for problem drinking, 482 men and 292 women met inclusion criteria and were randomized into a control (n=382) or an experimental (n=392) group. A total of 723 subjects (93%) participated in the 12-month follow-up procedures. <h3>Intervention.</h3> —The intervention consisted of two 10- to 15-minute counseling visits delivered by physicians using a scripted workbook that included advice, education, and contracting information. <h3>Main Outcome Measures.</h3> —Alcohol use measures, emergency department visits, and hospital days. <h3>Results.</h3> —There were no significant differences between groups at baseline on alcohol use, age, socioeconomic status, smoking status, rates of depression or anxiety, frequency of conduct disorders, lifetime drug use, or health care utilization. At the time of the 12-month follow-up, there were significant reductions in 7-day alcohol use (mean number of drinks in previous 7 days decreased from 19.1 at baseline to 11.5 at 12 months for the experimental group vs 18.9 at baseline to 15.5 at 12 months for controls;<i>t</i>=4.33;<i>P</i>&lt;.001), episodes of binge drinking (mean number of binge drinking episodes during previous 30 days decreased from 5.7 at baseline to 3.1 at 12 months for the experimental group vs 5.3 at baseline to 4.2 at 12 months for controls;<i>t</i>=2.81;<i>P</i>&lt;.001), and frequency of excessive drinking (percentage drinking excessively in previous 7 days decreased from 47.5% at baseline to 17.8% at 12 months for the experimental group vs 48.1% at baseline to 32.5% at 12 months for controls;<i>t</i>=4.53;<i>P</i>&lt;.001). The ϰ<sup>2</sup>test of independence revealed a significant relationship between group status and length of hospitalization over the study period for men (<i>P</i>&lt;.01). <h3>Conclusions.</h3> —This study provides the first direct evidence that physician intervention with problem drinkers decreases alcohol use and health resource utilization in the US health care system.
Asymptomatic Carotid Bruit and Risk of Stroke
Authors: Philip A. Wolf
Journal: JAMA (1981)

Carotid bruit was routinely sought in the Framingham cohort and during eight years appeared in 66 men and 105 women, all of whom were asymptomatic. The incidence increased with age equally in the two sexes from 3.5% at 44 to 54 years, to 7.0% at 65 to 79 years. The eight-year incidence was greater in diabetics and hypertensive subjects. Transient ischemic attacks appeared in eight (two alone) and stroke in 21 of the 171, a stroke rate more than twice expected for age and sex. More often than not, cerebral infarction occurred in a vascular territory different from that of the carotid bruit, often in the posterior circulation, and ruptured aneurysm, embolism from the heart, and lacunar infarction was the mechanism of stroke in nearly half the cases. Incidence of myocardial infarction was also increased twofold in those with asymptomatic carotid bruit. General mortality was also increased; 1.7-fold in men, and 1.9-fold in women, with 79% of the deaths owing to cardiovascular disease, including stroke. Carotid bruit is clearly an indicator of increased stroke risk but chiefly as a general and nonfocal sign of advanced atherosclerotic disease and not necessarily as an indicator of local arterial stenosis preceding cerebral infarction. (<i>JAMA</i>1981;245:1442-1445)
Alcohol Abuse, Other Drug Abuse, and Mental Disorders in Medical Practice
Authors: Douglas B. Kamerow
Journal: JAMA (1986)

Millions of Americans suffer and die of alcohol abuse, other drug abuse, and mental disorders that go undiagnosed and untreated. Studies showing that up to 19% of the US adult population have these disorders also have found that only one fifth of those affected have sought help for them in the previous six months. Many of these persons have disorders that are treatable with modern medications and therapy. Because more than half of all persons with these disorders obtain all of their care from the general medical sector, a great potential exists in primary care for prevention, detection, treatment, and referral of these patients. Primary care physicians, however, have not been very successful at diagnosing and treating substance abuse and mental disorders because of inadequate training, patients' attitudes, and the constraints of the health care system. Recommendations to improve this situation include continued research, improved physician education, and increased emphasis on care of these disorders by organized medicine. Although tobacco use is also a major health problem, data relating to nicotine addiction were not included in this report. (<i>JAMA</i>1986;255:2054-2057)
Cost-effectiveness of outpatient versus inpatient non-invasive ventilation setup in obesity hypoventilation syndrome: the OPIP trial
Authors: Patrick Brian Murphy, Maxime Patout, Gill Arbane, Swapna Mandal, Georgios Kaltsakas, Michael I Polkey, Mark Elliott, Jean-François Muir, Abdel Douiri, David Parkin, Jean-Paul Janssens, Jean Louis Pépin, Antoine Cuvelier, Clare Flach, Nicholas Hart
Journal: Thorax (2022)

Current guidelines recommend that patients with obesity hypoventilation syndrome (OHS) are electively admitted for inpatient initiation of home non-invasive ventilation (NIV). We hypothesised that outpatient NIV setup would be more cost-effective.Patients with stable OHS referred to six participating European centres for home NIV setup were recruited to an open-labelled clinical trial. Patients were randomised via web-based system using stratification to inpatient setup, with standard fixed level NIV and titrated during an attended overnight respiratory study or outpatient setup using an autotitrating NIV device and a set protocol, including home oximetry. The primary outcome was cost-effectiveness at 3 months with daytime carbon dioxide (PaCO2) as a non-inferiority safety outcome; non-inferiority margin 0.5 kPa. Data were analysed on an intention-to-treat basis. Health-related quality of life (HRQL) was measured using EQ-5D-5L (5 level EQ-5D tool) and costs were converted using purchasing power parities to £(GBP).Between May 2015 and March 2018, 82 patients were randomised. Age 59±14 years, body mass index 47±10 kg/m2 and PaCO2 6.8±0.6 kPa. Safety analysis demonstrated no difference in ∆PaCO2 (difference -0.27 kPa, 95% CI -0.70 to 0.17 kPa). Efficacy analysis showed similar total per-patient costs (inpatient £2962±£580, outpatient £3169±£525; difference £188.20, 95% CI -£61.61 to £438.01) and similar improvement in HRQL (EQ-5D-5L difference -0.006, 95% CI -0.05 to 0.04). There were no differences in secondary outcomes.There was no difference in medium-term cost-effectiveness, with similar clinical effectiveness, between outpatient and inpatient NIV setup. The home NIV setup strategy can be led by local resource demand and patient and clinician preference.NCT02342899 and ISRCTN51420481.
Embryonic and neonatal waves generate distinct populations of hepatic ILC1s
Authors: Colin Sparano, Darío Solís-Sayago, Anjali Vijaykumar, Chiara Rickenbach, Marijne Vermeer, Florian Ingelfinger, Gioana Litscher, André Fonseca, Caroline Mussak, Maud Mayoux, Christin Friedrich, César Nombela-Arrieta, Georg Gasteiger, Burkhard Becher, Sonia Tugues
Journal: Science Immunology (2022)

Group 1 innate lymphoid cells (ILCs) comprising circulating natural killer (cNK) cells and tissue-resident ILC1s are critical for host defense against pathogens and tumors. Despite a growing understanding of their role in homeostasis and disease, the ontogeny of group 1 ILCs remains largely unknown. Here, we used fate mapping and single-cell transcriptomics to comprehensively investigate the origin and turnover of murine group 1 ILCs. Whereas cNK cells are continuously replaced throughout life, we uncovered tissue-dependent development and turnover of ILC1s. A first wave of ILC1s emerges during embryogenesis in the liver and transiently colonizes fetal tissues. After birth, a second wave quickly replaces ILC1s in most tissues apart from the liver, where they layer with embryonic ILC1s, persist until adulthood, and undergo a specific developmental program. Whereas embryonically derived ILC1s give rise to a cytotoxic subset, the neonatal wave establishes the full spectrum of ILC1s. Our findings uncover key ontogenic features of murine group 1 ILCs and their association with cellular identities and functions.
Rhythmicity of intestinal IgA responses confers oscillatory commensal microbiota mutualism
Authors: Hugo A. Penny, Rita G. Domingues, Maria Z. Krauss, Felipe Melo-Gonzalez, Melissa A. E. Lawson, Suzanna Dickson, James Parkinson, Madeleine Hurry, Catherine Purse, Emna Jegham, Cristina Godinho-Silva, Miguel Rendas, Henrique Veiga-Fernandes, David A. Bechtold, Richard K. Grencis, Kai-Michael Toellner, Ari Waisman, Jonathan R. Swann, Julie E. Gibbs, Matthew R. Hepworth
Journal: Science Immunology (2022)

Interactions between the mammalian host and commensal microbiota are enforced through a range of immune responses that confer metabolic benefits and promote tissue health and homeostasis. Immunoglobulin A (IgA) responses directly determine the composition of commensal species that colonize the intestinal tract but require substantial metabolic resources to fuel antibody production by tissue-resident plasma cells. Here, we demonstrate that IgA responses are subject to diurnal regulation over the course of a circadian day. Specifically, the magnitude of IgA secretion, as well as the transcriptome of intestinal IgA + plasma cells, was found to exhibit rhythmicity. Oscillatory IgA responses were found to be entrained by time of feeding and were also found to be in part coordinated by the plasma cell–intrinsic circadian clock via deletion of the master clock gene Arntl . Moreover, reciprocal interactions between the host and microbiota dictated oscillatory dynamics among the commensal microbial community and its associated transcriptional and metabolic activity in an IgA-dependent manner. Together, our findings suggest that circadian networks comprising intestinal IgA, diet, and the microbiota converge to align circadian biology in the intestinal tract and to ensure host-microbial mutualism.
Autoreactive napsin A–specific T cells are enriched in lung tumors and inflammatory lung lesions during immune checkpoint blockade
Authors: Fiamma Berner, David Bomze, Christa Lichtensteiger, Vincent Walter, Rebekka Niederer, Omar Hasan Ali, Nina Wyss, Jens Bauer, Lena Katharina Freudenmann, Ana Marcu, Eva-Maria Wolfschmitt, Sebastian Haen, Thorben Gross, Marie-Therese Abdou, Stefan Diem, Stella Knöpfli, Tobias Sinnberg, Kathrin Hofmeister, Hung-Wei Cheng, Marieta Toma, Niklas Klümper, Mette-Triin Purde, Oltin Tiberiu Pop, Ann-Kristin Jochum, Steve Pascolo, Markus Joerger, Martin Früh, Wolfram Jochum, Hans-Georg Rammensee, Heinz Läubli, Michael Hölzel, Jacques Neefjes, Juliane Walz, Lukas Flatz
Journal: Science Immunology (2022)

Cancer treatment with immune checkpoint blockade (ICB) often induces immune-related adverse events (irAEs). We hypothesized that proteins coexpressed in tumors and normal cells could be antigenic targets in irAEs and herein described DITAS (discovery of tumor-associated self-antigens) for their identification. DITAS computed transcriptional similarity between lung tumors and healthy lung tissue based on single-sample gene set enrichment analysis. This identified 10 lung tissue–specific genes highly expressed in the lung tumors. Computational analysis was combined with functional T cell assays and single-cell RNA sequencing of the antigen-specific T cells to validate the lung tumor self-antigens. In patients with non–small cell lung cancer (NSCLC) treated with ICB, napsin A was a self-antigen that elicited strong CD8 + T cell responses, with ICB responders harboring higher frequencies of these CD8 + T cells compared with nonresponders. Human leukocyte antigen (HLA) class I ligands derived from napsin A were present in human lung tumors and in nontumor lung tissues, and napsin A tetramers confirmed the presence of napsin A–specific CD8 + T cells in blood and tumors of patients with NSCLC. Napsin A–specific T cell clonotypes were enriched in lung tumors and ICB-induced inflammatory lung lesions and could kill immortalized HLA-matched NSCLC cells ex vivo. Single-cell RNA sequencing revealed that these T cell clonotypes expressed proinflammatory cytokines and cytotoxic markers. Thus, DITAS successfully identified self-antigens, including napsin A, that likely mediate effective antitumor T cell responses in NSCLC and may simultaneously underpin lung irAEs.